Predicting functional decline in aging and Alzheimer's disease with PET-based Braak staging.

The progression of PET-based Braak stages correlates with cognitive deterioration in aging and Alzheimer's disease. Here, we investigate the association between PET-based Braak stages and functional impairment and assess whether PET-based Braak staging predicts a longitudinal decline in the performance of activities of daily living. In this cohort study, we evaluated cognitively unimpaired individuals and individuals with mild cognitive impairment or Alzheimer's disease dementia. Participants underwent [18F]MK6240 tau-PET, were assigned a PET-based Braak stage at baseline and were followed for a mean (SD) of 1.97 (0.66) years. Functional performance was evaluated with the Functional Activities Questionnaire, Everyday Cognition and functional Clinical Dementia Rating sum of boxes. Multiple linear regressions assessed the association of PET-based Braak stages with baseline functionality and with the longitudinal rate of change in functional scores, adjusting for age, sex and amyloid-ß load. We employed voxel-based regression models to investigate the association between functionality and tau-PET signal and assessed the voxel overlap with Braak regions of interest. We included 291 individuals (181 cognitively unimpaired, 56 amyloid-ß+ mild cognitive impairment and 54 amyloid-ß+ Alzheimer's disease) aged 70.60 (7.48) years. At baseline, PET-based Braak stages III-IV (ß = 0.43, P = 0.03) and V-VI (ß = 1.20, P < 0.0001) showed associations with poorer Functional Activities Questionnaire scores. Similarly, stages III-IV (ß = 0.43, P = 0.02) and V-VI (ß = 1.15, P < 0.0001) were associated with worse Everyday Cognition scores. Only stages V-VI were associated with higher functional Clinical Dementia Rating sum of boxes (ß = 1.17, P < 0.0001) scores. Increased tau-PET signals in all Braak regions of interest were linked to worse performance in all tools. The voxelwise analysis showed widespread cortical associations between functional impairment and tau-PET and high voxel overlap with Braak regions of interest. Baseline PET-based Braak stages V-VI predicted significant longitudinal functional decline as assessed by the Functional Activities Questionnaire (ß = 1.69, P < 0.0001), the Everyday Cognition (ß = 1.05, P = 0.001) and the functional Clinical Dementia Rating sum of boxes (ß = 1.29, P < 0.0001). Our results suggest that functional impairment increases with the severity of tau accumulation. These findings also indicate that PET-based Braak staging is a good predictor of functional impairment in the Alzheimer's disease continuum. Finally, our study provides evidence for the clinical significance of the PET-based Braak staging framework.

Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease.

Importance: Neuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms. Objective: To evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum. Design, Setting, and Participants: This cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions. Main Outcomes and Measures: All individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-ß ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET). Results: Of the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-ß PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (ß = 7.37; 95% CI, 1.34-13.41; P = .01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (ß = 6.86; 95% CI, 1.77-11.95; P = .008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (ß = 5.72; 95% CI, 0.33-11.10; P = .03). Conclusions and Relevance: In this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-ß- and microglia-targeted therapies could have an impact on relieving these symptoms.

Hippocampal subfield associations with memory depend on stimulus modality and retrieval mode.

Hippocampal atrophy is a well-known feature of age-related memory decline, and hippocampal subfields may contribute differently to this decline. In this cross-sectional study, we investigated the associations between hippocampal subfield volumes and performance in free recall and recognition memory tasks in both verbal and visual modalities in older adults without dementia. We collected MRIs from 97 (41 males) right-handed participants aged over 60. We segmented the right and left hippocampi into (i) dentate gyrus and cornu ammonis 4 (DG/CA4); (ii) CA2 and CA3 (CA2/CA3); (iii) CA1; (iv) strata radiatum, lacunosum and moleculare; and (v) subiculum. Memory was assessed with verbal free recall and recognition tasks, as well as visual free recall and recognition tasks. Amyloid-ß and hippocampal tau positivity were assessed using [18F]AZD4694 and [18F]MK6240 PET tracers, respectively. The verbal free recall and verbal recognition performances were positively associated with CA1 and strata radiatum, lacunosum and moleculare volumes. The verbal free recall and visual free recall were positively correlated with the right DG/CA4. The visual free recall, but not verbal free recall, was also associated with the right CA2/CA3. The visual recognition was not significantly associated with any subfield volume. Hippocampal tau positivity, but not amyloid-ß positivity, was associated with reduced DG/CA4, CA2/CA3 and strata radiatum, lacunosum and moleculare volumes. Our results suggest that memory performances are linked to specific subfields. CA1 appears to contribute to the verbal modality, irrespective of the free recall or recognition mode of retrieval. In contrast, DG/CA4 seems to be involved in the free recall mode, irrespective of verbal or visual modalities. These results are concordant with the view that DG/CA4 plays a primary role in encoding a stimulus' distinctive attributes, and that CA2/CA3 could be instrumental in recollecting a visual memory from one of its fragments. Overall, we show that hippocampal subfield segmentation can be useful for detecting early volume changes and improve our understanding of the hippocampal subfields' roles in memory.

APOEε4 potentiates amyloid ß effects on longitudinal tau pathology.

The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences the pathophysiological progression of Alzheimer's disease (AD) are poorly understood. Here we tested the association of APOEε4 carriership and amyloid-ß (Aß) burden with longitudinal tau pathology. We longitudinally assessed 94 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aß ([18F]AZD4694) and tau ([18F]MK-6240) at baseline, as well as a 2-year follow-up tau-PET scan. We found that APOEε4 carriership potentiates Aß effects on longitudinal tau accumulation over 2 years. The APOEε4-potentiated Aß effects on tau-PET burden were mediated by longitudinal plasma phosphorylated tau at threonine 217 (p-tau217+) increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. Our results suggest that the APOEε4 allele plays a key role in Aß downstream effects on the aggregation of phosphorylated tau in the living human brain.

Amyloid beta plaque accumulation with longitudinal [18F]AZD4694 PET.

Introduction: [18F]AZD4694 is an amyloid beta (Aß) imaging agent used in several observational studies and clinical trials. However, no studies have yet published data on longitudinal Aß accumulation measured with [18F]AZD4694. Methods: We assessed 146 individuals who were evaluated with [18F]AZD4694 at baseline and 2-year follow-up. We calculated annual rates of [18F]AZD4694 change for clinically defined and biomarker-defined groups. Results: Cognitively unimpaired (CU) older adults displayed subtle [18F]AZD4694 standardized uptake value ratio (SUVR) accumulation over the follow-up period. In contrast, Aß positive CU older adults displayed higher annual [18F]AZD4694 SUVR increases. [18F]AZD4694 SUVR accumulation in Aß positive mild cognitive impairment (MCI) and dementia was modest across the neocortex. Discussion: Larger increases in [18F]AZD4694 SUVR were observed in CU individuals who had abnormal amyloid positron emission tomography levels at baseline. [18F]AZD4694 can be used to monitor Aß levels in therapeutic trials as well as clinical settings, particularly prior to initiating anti-amyloid therapies.

Verbal memory formation across PET-based Braak stages of tau accumulation in Alzheimer's disease.

A classical early sign of typical Alzheimer's disease is memory decline, which has been linked to the aggregation of tau in the medial temporal lobe. Verbal delayed free recall and recognition tests have consistently probed useful to detect early memory decline, and there is substantial debate on how performance, particularly in recognition tests, is differentially affected through health and disease in older adults. Using in vivo PET-Braak staging, we investigated delayed recall and recognition memory dysfunction across the Alzheimer's disease spectrum. Our cross-sectional study included 144 cognitively unimpaired elderly, 39 amyloid-ß+ individuals with mild cognitive impairment and 29 amyloid-ß+ Alzheimer's disease patients from the Translational Biomarkers in Aging and Dementia cohort, who underwent [18F]MK6240 tau and [18F]AZD4694 amyloid PET imaging, structural MRI and memory assessments. We applied non-parametric comparisons, correlation analyses, regression models and voxel-wise analyses. In comparison with PET-Braak Stage 0, we found that reduced, but not clinically significant, delayed recall starts at PET-Braak Stage II (adjusted P < 0.0015), and that recognition (adjusted P = 0.011) displayed a significant decline starting at PET-Braak Stage IV. While performance in both delayed recall and recognition related to tau in nearly the same cortical areas, further analyses showed that delayed recall rendered stronger associations in areas of early tau accumulation, whereas recognition displayed stronger correlations in mostly posterior neocortical regions. Our results support the notion that delayed recall and recognition deficits are predominantly associated with tau load in allocortical and neocortical areas, respectively. Overall, delayed recall seems to be more dependent on the integrity of anterior medial temporal lobe structures, while recognition appears to be more affected by tau accumulation in cortices beyond medial temporal regions.

APOEε4 associates with microglial activation independently of Aß plaques and tau tangles.

Animal studies suggest that the apolipoprotein E ε4 (APOEε4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOEε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-ß (Aß; [18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28). We found that APOEε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aß and tau deposition. Furthermore, microglial activation mediated the Aß-independent effects of APOEε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOEε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOEε4 genotype exerts Aß-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.

Medial temporal tau predicts memory decline in cognitively unimpaired elderly.

Alzheimer's disease can be detected in living people using in vivo biomarkers of amyloid-ß and tau, even in the absence of cognitive impairment during the preclinical phase. [18F]-MK-6420 is a high-affinity PET tracer that quantifies tau neurofibrillary tangles, but its ability to predict cognitive changes associated with early Alzheimer's disease symptoms, such as memory decline, is unclear. Here, we assess the prognostic accuracy of baseline [18F]-MK-6420 tau-PET for predicting longitudinal memory decline in asymptomatic elderly individuals. In a longitudinal observational study, we evaluated a cohort of cognitively normal elderly participants (n = 111) from the translational biomarkers in ageing and dementia study (data collected between October 2017 and July 2020, with a follow-up period of 12 months). All participants underwent tau-PET with [18F]-MK-6420 and amyloid-ß PET with [18F]-AZD-4694. The exclusion criteria included the presence of head trauma, stroke or other neurological disorders. There were 111 eligible participants selected based on the availability of amyloid-ß PET, tau-PET, MRI and APOEɛ4 genotyping. Among these participants, the mean standard deviation age was 70.1 (8.6) years; 20 (18%) were tau-PET-positive and 71 of 111 (63.9%) were women. A significant association between the baseline Braak Stages I-II [18F]-MK-6240 standardized uptake value ratio positivity and change in composite memory score were observed at the 12-month follow-up, after correcting for age, sex and years of education [logical memory and Rey Auditory Verbal Learning Test, standardized beta = -0.52 (-0.82-0.21), P < 0.001, for dichotomized tau-PET and -1.22 (-1.84-(-0.61)], P < 0.0001, for continuous tau-PET]. Moderate cognitive decline was observed for A + T + over the follow-up period, whereas no significant change was observed for A-T+, A + T- and A-T-, although it should be noted that the A-T + group was small. Our results indicate that baseline tau neurofibrillary tangle pathology is associated with longitudinal changes in memory function, supporting the use of [18F]-MK-6420 PET to predict the likelihood of asymptomatic elderly individuals experiencing future memory decline. Overall, [18F]-MK-6420 PET is a promising tool for predicting memory decline in older adults without cognitive impairment at baseline. This is of critical relevance as the field is shifting towards a biological model of Alzheimer's disease defined by the aggregation of pathologic tau. Therefore, early detection of tau pathology using [18F]-MK-6420 PET provides us with hope that living patients with Alzheimer's disease may be diagnosed during the preclinical phase before it is too late.

The Association of Age-Related and Off-Target Retention with Longitudinal Quantification of [18F]MK6240 Tau PET in Target Regions.

6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([18F]MK6240) tau PET tracer quantifies the brain tau neurofibrillary tangle load in Alzheimer disease. The aims of our study were to test the stability of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off-target retention on the longitudinal quantification of [18F]MK6240 in target regions. Methods: We assessed reference, target, age-related, and off-target regions in 125 individuals across the aging and Alzheimer disease spectrum with longitudinal [18F]MK6240 SUVs and SUV ratios (SUVRs) (mean ± SD, 2.25 ± 0.40 y of follow-up). We obtained SUVR from meninges, exhibiting frequent off-target retention with [18F]MK6240. Additionally, we compared tracer uptake between 37 cognitively unimpaired young (CUY) (mean age, 23.41 ± 3.33 y) and 27 cognitively unimpaired older (CU) adults (amyloid-ß-negative and tau-negative, 58.50 ± 9.01 y) to identify possible nonvisually apparent, age-related signal. Two-tailed t testing and Pearson correlation testing were used to determine the difference between groups and associations between changes in region uptake, respectively. Results: Inferior cerebellar gray matter SUV did not differ on the basis of diagnosis and amyloid-ß status, cross-sectionally and over time. [18F]MK6240 uptake significantly differed between CUY and CU adults in the putamen or pallidum (affecting ∼75% of the region) and in the Braak II region (affecting ∼35%). Changes in meningeal and putamen or pallidum SUVRs did not significantly differ from zero, nor did they vary across diagnostic groups. We did not observe significant correlations between longitudinal changes in age-related or meningeal off-target retention and changes in target regions, whereas changes in all target regions were strongly correlated. Conclusion: Inferior cerebellar gray matter was similar across diagnostic groups cross-sectionally and stable over time and thus was deemed a suitable reference region for quantification. Despite not being visually perceptible, [18F]MK6240 has age-related retention in subcortical regions, at a much lower magnitude but topographically colocalized with significant off-target signal of the first-generation tau tracers. The lack of correlation between changes in age-related or meningeal and target retention suggests little influence of possible off-target signals on longitudinal tracer quantification. Nevertheless, the age-related retention in the Braak II region needs to be further investigated. Future postmortem studies should elucidate the source of the newly reported age-related [18F]MK6240 signal, and in vivo studies should further explore its impact on tracer quantification.

CSF tau368/total-tau ratio reflects cognitive performance and neocortical tau better compared to p-tau181 and p-tau217 in cognitively impaired individuals.

INTRODUCTION: Cerebrospinal fluid (CSF) tau biomarkers are reliable diagnostic markers for Alzheimer's disease (AD). However, their strong association with amyloid pathology may limit their reliability as specific markers of tau neurofibrillary tangles. A recent study showed evidence that a ratio of CSF C-terminally truncated tau (tau368, a tangle-enriched tau species), especially in ratio with total tau (t-tau), correlates strongly with tau PET tracer uptake. In this study, we set to evaluate the performance of the tau368/t-tau ratio in capturing tangle pathology, as indexed by a high-affinity tau PET tracer, as well as its association with severity of clinical symptoms. METHODS: In total, 125 participants were evaluated cross-sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (21 young, 60 cognitively unimpaired [CU] elderly [15 Aß+], 10 Aß+ with mild cognitive impairment [MCI], 14 AD dementia patients, and 20 Aß- individuals with non-AD cognitive disorders). All participants underwent amyloid and tau PET scanning, with [18F]-AZD4694 and [18F]-MK6240, respectively, and had CSF measurements of p-tau181, p-tau217, and t-tau. CSF concentrations of tau368 were quantified in all individuals with an in-house single molecule array assay. RESULTS: CSF tau368 concentration was not significantly different across the diagnostic groups, although a modest increase was observed in all groups as compared with healthy young individuals (all P < 0.01). In contrast, the CSF tau368/t-tau ratio was the lowest in AD dementia, being significantly lower than in CU individuals (Aß-, P < 0.001; Aß+, P < 0.01), as well as compared to those with non-AD cognitive disorders (P < 0.001). Notably, in individuals with symptomatic AD, tau368/t-tau correlated more strongly with [18F]-MK6240 PET SUVR as compared to the other CSF tau biomarkers, with increasing associations being seen in brain regions associated with more advanced disease (isocortical regions > limbic regions > transentorhinal regions). Importantly, linear regression models indicated that these associations were not confounded by Aß PET SUVr. CSF tau368/t-tau also tended to continue to become more abnormal with higher tau burden, whereas the other biomarkers plateaued after the limbic stage. Finally, the tau368/t-tau ratio correlated more strongly with cognitive performance in individuals with symptomatic AD as compared to t-tau, p-tau217 and p-tau181. CONCLUSION: The tau368/t-tau ratio captures novel aspects of AD pathophysiology and disease severity in comparison to established CSF tau biomarkers, as it is more closely related to tau PET SUVR and cognitive performance in the symptomatic phase of the disease.

Astrocyte biomarker signatures of amyloid-ß and tau pathologies in Alzheimer's disease.

Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-ß (Aß) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aß ([18F]AZD4694) and tau ([18F]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aß-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aß-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aß and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aß and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.

Comparing tau status determined via plasma pTau181, pTau231 and [18F]MK6240 tau-PET.

BACKGROUND: Tau in Alzheimer's disease (AD) is assessed via cerebrospinal fluid (CSF) and Positron emission tomography (PET). Novel methods to detect phosphorylated tau (pTau) in blood have been recently developed. We aim to investigate agreement of tau status as determined by [18F]MK6240 tau-PET, plasma pTau181 and pTau231. METHODS: We assessed cognitively unimpaired young, cognitively unimpaired, mild cognitive impairment and AD individuals with [18F]MK6240, plasma pTau181, pTau 231, [18F]AZD4694 amyloid-PET and MRI. A subset underwent CSF assessment. We conducted ROC curves to obtain cut-off values for plasma pTau epitopes. Individuals were categorized as positive or negative in all biomarkers. We then compared the distribution among concordant and discordant groups in relation to diagnosis, Aß status, APOEε4 status, [18F]AZD4694 global SUVR, hippocampal volume and CSF pTau181. FINDINGS: The threshold for positivity was 15.085 pg/mL for plasma pTau181 and 17.652 pg/mL for plasma pTau231. Most individuals had concordant statuses, however, 18% of plasma181/PET, 26% of plasma231/PET and 25% of the pTau231/pTau181 were discordant. Positivity to at least one biomarker was often accompanied by diagnosis of cognitive impairment, Aß positivity, APOEε4 carriership, higher levels of [18F]AZD4694 global SUVR, hippocampal atrophy and CSF pTau181. INTERPRETATION: Plasma pTau181, pTau231 and [18F]MK6240 seem to reflect different stages of tau progression. Plasma biomarkers can be useful in the context of diagnostic information and clinical trials, to evaluate the disease stage. Moreover, they seem to confidently evaluate tau-PET positivity. FUNDING: Moreover, this study was supported by Weston Brain Institute, Canadian Institute of Health Research and Fonds de Recherche du Québec.

Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum.

Importance: Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP. Objective: To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP. Design, Setting, and Participants: This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer's and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD. Main Outcomes and Measures: Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-ß 42/40 (Aß42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD. Results: A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisière participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aß-negative individuals (TRIAD: Aß-negative mean [SD], 185.1 [93.5] pg/mL, Aß-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: Aß-negative mean [SD], 121.9 [42.4] pg/mL, Aß-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aß-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] Aß-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU Aß-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI Aß-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU Aß-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aß-positive from Aß-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aß pathology. Conclusions and Relevance: This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aß pathology even among individuals in the early stages of AD.